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A BW Reporter System for Studying Receptor-Ligand Interactions
Published on: January 7, 2019
Somatostatin receptor type 2 as a radiotheranostic PET reporter gene for oncologic interventions
Pedram Heidari1, Anchisa Kunawudhi1, Jordi Martinez-Quintanilla1
1Department of Radiology, Massachusetts General Hospital, Boston, MA.
Abstract:
Reporter gene systems can serve as therapy targets. However, the therapeutic use of reporters has been limited by the challenges of transgene delivery to a majority of cancer cells. This study specifically assesses the efficacy of targeting human somatostatin receptor subtype 2 (hSSTR2) with peptide receptor radionuclide therapy (PRRT) when a small subpopulation of cells bears the transgene. Methods: The hSSTR2 transgene was delivered to A549 and Panc-1tumors using the lentiviral vector, LV-hSSTR2-IRES-GFP or murine mesenchymal stem cells (mMSC)s using a retroviral vector. SSTR2 expression was assessed using Western blot and correlated to GFP fluorescence and 68Ga-DOTATOC uptake. Wild type (WT), transduced (TD), and mixed population A549 or Panc-1 xenografts were implanted in nude mice. Separate groups with A549WT and Panc-1WT tumors received intratumoral injection of SSTR2-expressing mMSCs. Tumor-bearing mice were treated with 90Y-DOTATOC or saline and evaluated with 68Ga-DOTATOC PET before and after treatment. Results: Cell studies showed a strong correlation between 68Ga-DOTATOC uptake and SSTR2 expression in A549 (p < 0.004) and Panc-1 cells (p < 0.01). 68Ga-DOTATOC PET SUVmean was 8- and 5-fold higher in TD compared to WT A549 and Panc-1 tumors, respectively (p < 0.001). After 90Y-DOTATOC treatment, 100% TD and mixed population TD xenografts showed growth cessation while the WT xenografts did not. A549WT and Panc-1WT tumors with SSTR2-expressing mMSCs treated with 90Y-DOTATOC showed significantly lower tumor volumes compared to controls (p < 0.05). 68Ga-DOTATOC PET SUVmean of treated TD tumors monotonically declined and was significantly lower than that of non-treated xenografts. Conclusions: We showed that SSTR2 delivery to a small population of cells in tumor in conjunction with PRRT is effective in tumor growth cessation. The availability of various transgene delivery methods for hSSTR2 and radiotherpaeutic somatostatin analogs highlights the direct translational potential of this paradigm in the treatment of various cancers.
Insights
Targeting human somatostatin receptor subtype 2 (hSSTR2) with peptide receptor radionuclide therapy (PRRT) effectively halts tumor growth, even when only a small cancer cell population expresses the transgene. This approach shows significant translational potential for various cancer treatments.
Area of Science:
- Oncology
- Molecular Biology
- Radiotherapy
Background:
- Reporter gene systems hold therapeutic potential but face limitations in efficient transgene delivery to most cancer cells.
- Human somatostatin receptor subtype 2 (hSSTR2) is a target for peptide receptor radionuclide therapy (PRRT).
- Challenges exist in achieving therapeutic efficacy when only a minor subpopulation of cancer cells expresses the target transgene.
Purpose of the Study:
- To assess the efficacy of PRRT targeting hSSTR2 when the transgene is present in only a small fraction of tumor cells.
- To evaluate the effectiveness of lentiviral vectors and mesenchymal stem cells for delivering the hSSTR2 transgene.
- To correlate SSTR2 expression with diagnostic imaging (68Ga-DOTATOC PET) and therapeutic response (90Y-DOTATOC).
Main Methods:
- Delivered hSSTR2 transgene to A549 and Panc-1 tumor cells using lentiviral vectors or murine mesenchymal stem cells (mMSCs).
- Assessed SSTR2 expression via Western blot, correlating it with GFP fluorescence and 68Ga-DOTATOC uptake.
- Treated mice bearing wild-type (WT), transduced (TD), or mixed-population xenografts with 90Y-DOTATOC or saline, monitored by 68Ga-DOTATOC PET.
Main Results:
- Strong correlation observed between 68Ga-DOTATOC uptake and SSTR2 expression in both cell lines (p < 0.004 and p < 0.01).
- 68Ga-DOTATOC PET SUVmean was significantly higher in TD tumors compared to WT tumors (8-fold in A549, 5-fold in Panc-1; p < 0.001).
- 90Y-DOTATOC treatment resulted in 100% growth cessation in TD and mixed-population xenografts; WT tumors did not respond. Treated TD tumors showed decreased SUVmean post-therapy.
Conclusions:
- hSSTR2 delivery to a small cell population within a tumor, combined with PRRT, effectively halts tumor growth.
- The study demonstrates the translational potential of this therapeutic paradigm for various cancers, leveraging available transgene delivery methods and radiotherapeutic analogs.
- PRRT targeting hSSTR2 is effective even with limited transgene expression, offering a promising strategy for cancer treatment.
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